A major obstacle in drug discovery for Alzheimer's disease (AD) and other CNS disorders is the lack of a renewable source of scalable, high quality neuronal cells that recapitulate the pathophysiology of the target disease. Immortalized or genetically transformed neuronal lines generally lack important physiological properties of primary neurons. However, physiologically relevant dissociated primary neuron cultures are limited by cellular heterogeneity, cell number and scalability (Pouton, C. W. & Haynes, J. M. Nat. Rev. Drug. Discov. 6, 605-616 (2007)).
In addition to the issues surrounding physiologically relevant dissociated primary neuron cultures, it is also known that in AD, elevation of amyloid β-peptide (Aβ) and Aβ-triggered synaptic dysfunction are key pathogenic phenotypes (Hardy, J. & Selkoe, D. J. Science 297, 353-6 (2002)). Aβ is produced by sequential proteolytic cleavage of β-amyloid precursor protein (APP) by a set of membrane-bound proteases termed β- and γ-secretases. Various therapeutic approaches for AD are currently under development and include compounds that target β-amyloid pathway (Mangialasche, F., Solomon, A., Winblad, B., Mecocci, P, & Kivipelto, M. Lancet Neurol. 9, 702-16 (2010)). Accordingly, it will be important that any renewable source of scalable, high quality neuronal cells that recapitulate the pathophysiology of the target disease also recapitulate the targeted β-amyloid pathway.
The instant invention addresses both of these issues by providing highly physiological and AD-relevant platforms that are suitable for high throughput small molecule and functional genetic screens, as well as providing specific small molecule compounds identified by such screens.